Animal models of human diseases are invaluable and inevitable elements in identifying and testing novel treatments for serious diseases, including severe infections. Planning and conducting investigator-initiated human trials are generally accepted as being enormously challenging. In contrast, it is often underestimated how much planning, including background and modifying experiments, is needed to establish a relevant infectious disease animal model. However, representative animal infectious models, well designed to test generated hypotheses, are useful to improve our understanding of pathogenesis, virulence factors and host response and to identify novel treatment candidates and therapeutic strategies. Such results can subsequently proceed to clinical testing if suitable. The present review aims at presenting all the pulmonary Pseudomonas aeruginosa infectious models we have knowledge of and the detailed descriptions of established animal models in our laboratory focusing on macrolide therapy are presented.